Inhibition of fatty acid synthase suppresses osteosarcoma cell invasion and migration via downregulation of the PI3K/Akt 
signaling pathway in vitro

Liu,Zhi  Li; Mao,Jian  Hua; Peng,Ai  Fen; Yin,Qing  Shui; Zhou,Yang; Long,Xin  Hua; Huang,Shan  Hu

doi:10.3892/mmr.2012.1220

Inhibition of fatty acid synthase suppresses osteosarcoma cell invasion and migration via downregulation of the PI3K/Akt signaling pathway in vitro

Authors:
- Zhi Li Liu
- Jian Hua Mao
- Ai Fen Peng
- Qing Shui Yin
- Yang Zhou
- Xin Hua Long
- Shan Hu Huang
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Affiliations: Department of Orthopedics, First Affiliated Hospital of Nanchang University, Nanchang 330006, P.R. China, Jiangxi University of Traditional Chinese medicine, Nanchang 330006, P.R. China, Hospital of Orthopedic Surgery, Guangzhou General Hospital of Guangzhou Military Region, Guangzhou 510080, P.R. China
Published online on: December 3, 2012 https://doi.org/10.3892/mmr.2012.1220
Pages: 608-612

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Abstract

In the present study, the effect of fatty acid synthase (FASN) inhibition on cell invasion and migration in vitro was investigated. A recombinant plasmid containing a microRNA targeting the FASN gene was used to inhibit FASN expression in U2‑OS cells. Cell migration and invasion were investigated using wound healing and Transwell invasion assays. We found that cell invasion and migration were suppressed by inhibiting FASN. In addition, the effect of inhibition of FASN on phosphorylation of Akt was investigated by detecting the expression levels of pAkt using western blot analysis. Furthermore, protein expression levels of nuclear factor‑κB (NF‑κB; p65) and matrix metalloproteinase (MMP)‑2 and ‑9 were also measured by western blot analysis. Results demonstrated that expression levels of pAkt, NF‑κB (p65) and MMP‑2 and ‑9 proteins were reduced significantly by inhibiting FASN. Therefore, we confirmed that inhibition of FASN by RNA interference suppresses osteosarcoma cell metastasis via downregulation of the phosphoinositide 3‑kinase/Akt/NF‑κB signaling pathway in vitro.

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1	Meyers PA, Schwartz CL, Krailo M, et al: Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol. 23:2004–2011. 2005. View Article : Google Scholar : PubMed/NCBI
2	Bacci G, Forni C, Longhi A, et al: Local recurrence and local control of non-metastatic osteosarcoma of the extremities: a 27-year experience in a single institution. J Surg Oncol. 96:118–123. 2007.PubMed/NCBI
3	Jawad MU, Cheung MC, Clarke J, et al: Osteosarcoma: improvement in survival limited to high-grade patients only. J Cancer Res Clin Oncol. 137:597–607. 2011. View Article : Google Scholar : PubMed/NCBI
4	Mialou V, Philip T, Kalifa C, et al: Metastatic osteosarcoma at diagnosis: prognostic factors and long-term outcome - the French pediatric experience. Cancer. 104:1100–1109. 2005. View Article : Google Scholar : PubMed/NCBI
5	Hegyi M, Semsei AF, Jakab Z, et al: Good prognosis of localized osteosarcoma in young patients treated with limb-salvage surgery and chemotherapy. Pediatr Blood Cancer. 57:415–422. 2011. View Article : Google Scholar : PubMed/NCBI
6	Stokkel MP, Linthorst MF, Borm JJ, et al: A reassessment of bone scintigraphy and commonly tested pretreatment biochemical parameters in newly diagnosed osteosarcoma. J Cancer Res Clin Oncol. 128:393–399. 2002. View Article : Google Scholar : PubMed/NCBI
7	Yeh CS, Wang JY, Cheng TL, et al: Fatty acid metabolism pathway play an important role in carcinogenesis of human colorectal cancers by microarray-bioinformatics analysis. Cancer Lett. 233:297–308. 2006. View Article : Google Scholar : PubMed/NCBI
8	Hess D and Igal RA: Genistein downregulates de novo lipid synthesis and impairs cell proliferation in human lung cancer cells. Exp Biol Med (Maywood). 236:707–713. 2011.PubMed/NCBI
9	Alo PL, Amini M, Piro F, et al: Immunohistochemical expression and prognostic significance of fatty acid synthase in pancreatic carcinoma. Anticancer Res. 27:2523–2527. 2007.PubMed/NCBI
10	Walter K, Hong SM, Nyhan S, et al: Serum fatty acid synthase as a marker of pancreatic neoplasia. Cancer Epidemiol Biomarkers Prev. 18:2380–2385. 2009. View Article : Google Scholar : PubMed/NCBI
11	Okawa Y, Hideshima T, Ikeda H, et al: Fatty acid synthase is a novel therapeutic target in multiple myeloma. Br J Haematol. 141:659–671. 2008. View Article : Google Scholar
12	Migita T, Ruiz S, Fornari A, et al: Fatty acid synthase: a metabolic enzyme and candidate oncogene in prostate cancer. J Natl Cancer Inst. 101:519–532. 2009. View Article : Google Scholar : PubMed/NCBI
13	Silva SD, Cunha IW, Younes RN, et al: ErbB receptors and fatty acid synthase expression in aggressive head and neck squamous cell carcinomas. Oral Dis. 16:774–780. 2010. View Article : Google Scholar : PubMed/NCBI
14	Orita H, Coulter J, Tully E, et al: Inhibiting fatty acid synthase for chemoprevention of chemically induced lung tumors. Clin Cancer Res. 14:2458–2464. 2008. View Article : Google Scholar : PubMed/NCBI
15	Saati GE and Archer MC: Inhibition of fatty acid synthase and Sp1 expression by 3,3′-diindolylmethane in human breast cancer cells. Nutr Cancer. 63:790–794. 2011.
16	Notarnicola M, Pisanti S, Tutino V, et al: Effects of olive oil polyphenols on fatty acid synthase gene expression and activity in human colorectal cancer cells. Genes Nutr. 6:63–69. 2011. View Article : Google Scholar : PubMed/NCBI
17	Notarnicola M, Messa C, Refolo MG, et al: Polyunsaturated fatty acids reduce fatty acid synthase and hydroxy-methyl-glutaryl CoA-reductase gene expression and promote apoptosis in HepG2 cell line. Lipids Health Dis. 10:102011. View Article : Google Scholar : PubMed/NCBI
18	Zecchin KG, Rossato FA, Raposo HF, et al: Inhibition of fatty acid synthase in melanoma cells activates the intrinsic pathway of apoptosis. Lab Invest. 91:232–240. 2011. View Article : Google Scholar : PubMed/NCBI
19	Carvalho MA, Zecchin KG, Seguin F, et al: Fatty acid synthase inhibition with Orlistat promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model. Int J Cancer. 123:2557–2565. 2008. View Article : Google Scholar : PubMed/NCBI
20	Murata S, Yanagisawa K, Fukunaga K, et al: Fatty acid synthase inhibitor cerulenin suppresses liver metastasis of colon cancer in mice. Cancer Sci. 101:1861–1865. 2010. View Article : Google Scholar : PubMed/NCBI
21	Zhang XX, Fu Z, Zhang Z, et al: Microcystin-LR promotes melanoma cell invasion and enhances matrix metalloproteinase-2/-9 expression mediated by nf-kappab activation. Environ Sci Technol. 46:11319–11326. 2012. View Article : Google Scholar : PubMed/NCBI
22	Kao SJ, Su JL, Chen CK, et al: Osthole inhibits the invasive ability of human lung adenocarcinoma cells via suppression of NF-kappaB-mediated matrix metalloproteinase-9 expression. Toxicol Appl Pharmacol. 261:105–115. 2012. View Article : Google Scholar : PubMed/NCBI
23	Kuan YH, Huang FM, Li YC, et al: Proinflammatory activation of macrophages by bisphenol A-glycidyl-methacrylate involved NFkappaB activation via PI3K/Akt pathway. Food Chem Toxicol. 50:4003–4009. 2012. View Article : Google Scholar : PubMed/NCBI
24	Swinnen JV, Van Veldhoven PP, Timmermans L, et al: Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Biochem Biophys Res Commun. 302:898–903. 2003. View Article : Google Scholar : PubMed/NCBI
25	Uddin S, Siraj AK, Al-Rasheed M, et al: Fatty acid synthase and AKT pathway signaling in a subset of papillary thyroid cancers. J Clin Endocrinol Metab. 93:4088–4097. 2008. View Article : Google Scholar : PubMed/NCBI
26	Wang HQ, Altomare DA, Skele KL, et al: Positive feedback regulation between AKT activation and fatty acid synthase expression in ovarian carcinoma cells. Oncogene. 24:3574–3582. 2005. View Article : Google Scholar : PubMed/NCBI
27	Menendez JA, Vellon L, Mehmi I, et al: Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc Natl Acad Sci USA. 101:10715–10720. 2004. View Article : Google Scholar : PubMed/NCBI
28	Bai X, Ma D, Liu A, et al: Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science. 318:977–980. 2007. View Article : Google Scholar : PubMed/NCBI
29	Li W, Tai Y, Zhou J, et al: Repression of endometrial tumor growth by targeting SREBP1 and lipogenesis. Cell Cycle. 11:2348–2358. 2012. View Article : Google Scholar : PubMed/NCBI
30	Liu ZL, Wang G, Shu Y, et al: Enhanced antitumor activity of epirubicin combined with cerulenin in osteosarcoma. Mol Med Report. 5:326–330. 2012.PubMed/NCBI
31	Bandyopadhyay S, Pai SK, Watabe M, et al: FAS expression inversely correlates with PTEN level in prostate cancer and a PI 3-kinase inhibitor synergizes with FAS siRNA to induce apoptosis. Oncogene. 24:5389–5395. 2005. View Article : Google Scholar
32	Porstmann T, Griffiths B, Chung YL, et al: PKB/Akt induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation of SREBP. Oncogene. 24:6465–6481. 2005.PubMed/NCBI
33	Tomek K, Wagner R, Varga F, et al: Blockade of fatty acid synthase induces ubiquitination and degradation of phosphoinositide-3-kinase signaling proteins in ovarian cancer. Mol Cancer Res. 9:1767–1779. 2011. View Article : Google Scholar : PubMed/NCBI
34	Zaytseva YY, Rychahou PG, Gulhati P, et al: Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Res. 72:1504–1517. 2012. View Article : Google Scholar : PubMed/NCBI
35	Uddin S, Jehan Z, Ahmed M, et al: Overexpression of fatty acid synthase in Middle Eastern epithelial ovarian carcinoma activates AKT and Its inhibition potentiates cisplatin-induced apoptosis. Mol Med. 17:635–645. 2011. View Article : Google Scholar
36	Andela VB, Gordon AH, Zotalis G, et al: NFkappaB: a pivotal transcription factor in prostate cancer metastasis to bone. Clin Orthop Relat Res. 415(Suppl): S75–S85. 2003. View Article : Google Scholar : PubMed/NCBI
37	Felx M, Guyot MC, Isler M, et al: Endothelin-1 (ET-1) promotes MMP-2 and MMP-9 induction involving the transcription factor NF-kappaB in human osteosarcoma. Clin Sci (Lond). 110:645–654. 2006. View Article : Google Scholar : PubMed/NCBI